title: Synthesis and cardiac electrophysiological activity of aryl-substituted derivatives of the class III antiarrhythmic agent sematilide. Potential class I/III agents.
abstract: Twelve novel derivatives of the selective class III antiarrhythmic agent sematilide were prepared in an attempt to incorporate both class I and class III electrophysiological properties into a single molecule. Electrophysiological activity was determined by standard microelectrode techniques in canine cardiac Purkinje fibers. Initial assessment of class I efficacy was carried out in a ouabain-induced arrhythmia model in guinea pigs. All of the compounds prolonged action potential duration in Purkinje fibers (class III activity), and three were active against ouabain-induced arrhythmias (class I activity). Selected compounds were evaluated further in dogs for efficacy against arrhythmias occurring 24 h following coronary ligation (automatic arrhythmias) and induced by using programmed electrical stimulation techniques (reentrant arrhythmias). The most effective compounds from the series are 3g and -j, which were effective in both canine models. Molecular modeling and structure-activity relationships are discussed.
authors.affiliation: Department of Medicinal Chemistry, Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
authors.forename: G B
authors.initials: GB
authors.lastname: Phillips
authors.forename: T K
authors.initials: TK
authors.lastname: Morgan
authors.forename: K
authors.initials: K
authors.lastname: Nickisch
authors.forename: J M
authors.initials: JM
authors.lastname: Lind
authors.forename: R P
authors.initials: RP
authors.lastname: Gomez
authors.forename: R A
authors.initials: RA
authors.lastname: Wohl
authors.forename: T M
authors.initials: TM
authors.lastname: Argentieri
authors.forename: M E
authors.initials: ME
authors.lastname: Sullivan
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000145:classification / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D015195:Drug Design; D004594:Electrophysiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010042:Ouabain; D011342:Procainamide / Q000031:analogs & derivatives*; D011690:Purkinje Fibers; D013329:Structure-Activity Relationship
chemical_list: D000889:Anti-Arrhythmia Agents; C062818:sematilide; D010042:Ouabain; D011342:Procainamide